Recent advances in organic synthesis and screening of compounds have led to the discovery of new classes of agents useful as inhibitors of enzymes, agonists or antagonists of cell surface receptors, and the like. Although peptide-based ligands can have good activity in modulation of biochemical events, the susceptibility of polypeptides to rapid in vivo degradation has prompted researchers to seek non-peptidic active compounds.
Heteroaromatic compounds are ubiquitous in biochemistry, pharmacology, agricultural chemistry, and the like. Synthetic heteroaromatic compounds have been used as analgesics, antibiotics, anti-viral compounds, pesticides, and herbicides, among other uses. Although many methods are known for synthesizing heteroaromatic compounds, some of these methods may not be readily adaptable to the production of a variety of compounds (i.e., compounds bearing a variety of functional groups). Known methods may also not be well-suited to combinatorial syntheses, by which large numbers of compounds can be rapidly synthesized.
One method for synthesis of substituted thiophene compounds that has been reported (Gewald, K, E. Schinke, and H. Bottcher, Chem Ber., 1966 99, 94; Sampson, N. and P. Bartlett, J. Org Chem, 1991 56, 7179) involved reaction of a ketone or .beta.-ketoester with a cyanoacetate ester and elemental sulfur. Reported reaction solvents included ethanol, t-butanol, and dimethylformamide. However, reported yields were often only low to moderate. A related method for the synthesis of pyrroles has been reported (Roth, H. and K. Eger, Arch. Pharm., 1975 308. 179; Muller, C., et al., J. Med Chem. 1996 39, 2482). Again, however, yields are not uniformly high for all substrates.
Accordingly, improved methods for synthesis of heterocycles are desirable.